Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer's disease

Tai, Jingjing and Liu, Weizhen and Li, Yanwei and Li, Lin and Hölscher, Christian (2018) Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer's disease. Brain Research, 1678. pp. 64-74. ISSN 0006-8993

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Abstract

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer disease (AD). Previous studies have shown that the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) that have anti-diabetic properties show very promising effects in animal models of AD. Glucagon (Gcg) is a hormone and growth-factor, and the Gcg receptor is expressed in the brain. Here we test the effects of a triple receptor agonist (TA), which activates GIP-1, GIP and glucagon receptors at the same time. In the present study, the effects of the TA were evaluated in the APP/PS1 transgenic mouse model of AD. The TA was injected once-daily (10 nmol/kg i.p.) for two months. The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test. Moreover, the drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2 and enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD. Neurogenesis in the dentate gyrus was furthermore enhanced as shown in the increase of doublecortin positive cells. Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuroinflammation (activated microglia and astrocytes), and oxidative stress in the cortex and hippocampus. Thus, these findings show that novel TAs are a promising lead for the design of future treatment strategies in AD.

Item Type:
Journal Article
Journal or Publication Title:
Brain Research
Additional Information:
This is the author’s version of a work that was accepted for publication in Brain Research. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Brain Research, 1678, 2018 DOI: 10.1016/j.brainres.2017.10.012
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1312
Subjects:
ID Code:
88340
Deposited By:
Deposited On:
20 Oct 2017 12:18
Refereed?:
Yes
Published?:
Published
Last Modified:
22 Nov 2020 05:10